What Can Be Done to Predict Optimal CAR-T Responses?

In recent years, chimeric antigen receptor T cells (CAR-T) and bispecific T-cell engagers (bispecifics) have transformed treatment options for relapsed or refractory multiple myeloma (RRMM). 

These therapies harness the immune system to target and destroy myeloma cells, offering new hope to many patients. However, not all patients respond as well as hoped, and some eventually face treatment resistance or failure. Researchers are working hard to uncover why this happens and how to improve outcomes.

Understanding the Relationship between Genomics and Outcomes 

A recent study presented at the American Society of Hematology (ASH) conference, Genomic Determinants of Resistance to Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) Therapies in Patients with Relapsed/Refractory Multiple Myeloma, analyzed the genetic makeup of myeloma cells from 96 patients treated with either CAR-T therapy (74 patients) or bispecific antibodies (22 patients). The goal was to understand why some patients do not respond to treatment or experience relapse. Watch the video here and read on to learn more about this revealing study: 

Here are the main insights:

Treatment Outcomes for CAR-T Therapy

• Patients treated with CAR-T therapy had a median progression-free survival (PFS) of 394 days, meaning half the patients stayed in response for over a year.

• Unfortunately, 25% of these patients experienced relapse within the first 100 days of treatment, a condition known as refractory disease.

• Factors linked to shorter remission times included:

• Pre-treatment extramedullary disease (EMD) (myeloma outside the bone marrow).

• Prior exposure to other anti-BCMA therapies.

Genetic Changes That Influence Resistance

The researchers identified several genetic changes that can make myeloma resistant to CAR-T therapy:

• BCMA loss: The BCMA protein is a key target for CAR-T therapy. In 5% of patients, genetic changes caused the loss of BCMA in myeloma cells, making CAR-T treatment ineffective. This was especially common in patients previously treated with anti-BCMA drugs like belantamab mafodotin (BLENREP).

• NF-kB pathway changes: Myeloma cells with BCMA loss also had changes in other genes (e.g., CYLD, TRAF3) that regulate the NF-kB signaling pathway. This helped the cancer survive despite the absence of BCMA.

High-Risk Genetic Features

The study identified five major categories of genetic changes that influence treatment outcomes:

• Favorable: Patients with RPL10 mutations had excellent outcomes, with 84% remaining in remission at one year.

• Unfavorable:

  • Genomic instability (e.g., TP53 mutations).

  • NF-kB pathway alterations (e.g., CYLD, TRAF3 mutations).

  • Loss of key transcription factors (e.g., SP140, KMT2C mutations).

  • Plasma cell differentiation changes (e.g., TNFRSF17, CD38 mutations).

Patients with genetic changes from two or more unfavorable groups were much more likely to experience early relapse, with a median progression-free survival of just 75 days compared to 763 days for others.

Comparing CAR-T and Bispecific Antibody Therapies

Interestingly, CAR-T and bispecific antibody therapies have different mechanisms of resistance:

• For CAR-T, resistance was less commonly linked to BCMA mutations.

• For bispecifics, BCMA mutations were a significant driver of relapse, accounting for more than 50% of relapses.

Can a Previous Stem Cell Transplant Affect CAR-T Outcomes? 

Another study presented at ASH, Previous HDM/ASCT Adversely Impacts PFS with BCMA-Directed CAR T-Cell Therapy in Multiple Myeloma, explored whether prior treatments, particularly high-dose melphalan and autologous stem cell transplantation (SCT), impact CAR-T outcomes. 

The study included 104 myeloma patients treated with BCMA-directed CAR-T therapy between 2017 and 2023. Here’s what they found:

• Prior SCT was common: Over half the patients (52%) had previously undergone stem cell transplant, with a median gap of 5.2 years between the two treatments.
• Shorter Progression-Free Survival (PFS): Patients who had undergone a stem cell transplant had a median PFS of 9.5 months compared to 21 months in those who had not. This difference remained significant even after adjusting for factors like high-risk cytogenetics, disease stage, and other prior treatments.
• T-cell exhaustion: Stem cell transplant can lead to exhausted and senescent T-cells, which may reduce the effectiveness of CAR-T therapy.
• No impact on overall survival or toxicity: Prior stem cell transplant didn’t affect overall survival or the rates of side effects with CAR-T, such as cytokine release syndrome (CRS) and neurotoxicity (ICANS).

These findings suggest that prior stem cell transplant may impact the durability of CAR-T responses, but it doesn’t affect the ability to achieve an initial response.

Because this is a retrospective study from one center, these results should be interpreted with caution. A wider-scale study is needed to confirm these results.

What Does This Mean for Myeloma Patients and Caregivers?

These findings highlight the importance of personalized treatment strategies for myeloma. Comprehensive genetic testing can help identify high-risk patients and predict how well they might respond to CAR-T or bispecific antibody therapies. 

Additionally, discussing the impact of prior treatments like stem cell transplant with your healthcare team can help set realistic expectations and inform treatment planning.

"While there is still much to learn", adds myeloma patient and HealthTree Coach, Don Bathurst, "this research represents a significant step toward making advanced therapies more effective for all myeloma patients."

The Path Forward

The studies’ results offer hope for improving outcomes by:

• Using genetic profiling to tailor treatments
• Developing therapies that target the genetic changes linked to resistance
• Exploring strategies to overcome the effects of prior treatments like stem cell transplant
• Identifying ways to mitigate T-cell exhaustion for better CAR-T responses

Patient Perspective

Doug Keller, a myeloma patient passionate about the importance of myeloma education (and HealthTree Coach) shares,

"These studies highlight the importance of sequencing therapies. First, when considering CAR-T versus a BCMA-directed bispecific, know that having the bispecific first may decrease the effectiveness of a BCMA-directed CAR-T later. Second, as the CAR-T therapies move to earlier line use (second or third line for the two approved CAR-Ts), patients may want to consider a CAR-T as an alternative to a stem cell transplant. It may still be advisable to harvest stem cells for later use. It is important to know that these studies are for the BCMA therapies only and may or may not apply to emerging therapies directed towards other targets.

Some myeloma specialists now have the tools to analyze genetic markers on myeloma cells that can help guide decisions on which therapies are most likely to be successful. This is an emerging area of research that will eventually become more common and be of use as more therapies are developed.

As always, discussing this information with a myeloma specialist will help you make the most informed decision about your treatments."

To stay on top of myeloma ASH coverage, check out our HealthTree Conference Coverage. To connect with a myeloma coach like Don or Doug, visit the HealthTree Coach site.